1. Field of the Invention
The present invention relates to novel azolyl methyl phenyl derivatives, methods for producing the azolyl derivatives, aromatase inhibitory agents containing the azolyl derivatives, and pharmaceutical compositions containing the azolyl derivatives which compositions are useful as prophylactic and/or therapeutical agents of estrogen-dependent diseases.
2. Description of the Related Art
Aromatase is one of P-450 enzymes and catalyzes the aromatization of the A ring of the steroid skeleton in a series of the steroid biosynthetic pathway starting from the cleavage of the side chain of cholesterol; in other words, aromatase catalyzes the conversion from androstenedione to estrone and the conversion from testosterone to estradiol. Hence, aromatase is a rate limiting enzyme for the estrogen biosynthesis.
Therefore, a compound having an aromatase inhibitory activity should have an inhibitory activity on estrogen biosynthesis. Because it is anticipated that the compound lowers the blood estrogen level when administered to human or animals, it is believed that the compound may be applicable to estrogen dependent diseases which onset and exacerbation have relation with estrogen.
Such estrogen-dependent diseases include estrogen dependent-cancers (ex. breast cancer, ovarian cancer, endometrium cancer. etc.), endometriosis, uterine leiomyoma, benign breast diseases, mastopathy, premature labor, benign prostatic hyperplasia, prostate cancer, precocious puberty, gynecomastia, male infertility relating to oligospermia and cholelithiasis.
For therapeutical treatment of estrogen-dependent diseases, use has been made of a method for suppressing estrogen action in a target cell and a method for decreasing the estrogen level in blood. In a representative example of the former method, the administration of an estrogen antagonist such as tamoxifen has been in practice. However, clinically satisfactory effect cannot be brought about from such administration alone. In a representative example of the latter method, ovariectomy is generally performed so as to block estrogen generation via surgical treatment. Ovary is the main organ to produce estrogen. Such surgical treatment, however, causes a problem of damages on quality of life (abbreviated as "QOL" hereinafter) because a functional organ such as ovary essential for females is resected. Additionally, limitation and problems are remarked for its clinical application such that the decrease of blood estrogen level even by ovariectomy involves much difficulty in post menopausal patients; that the method is not applicable to male patients; and that the method is not applicable to estrogen produced by tumor cells themselves. On the other hand, greater attention has been focused on an internal treatment of estrogen-dependent diseases on the basis of the finding that an aromatase inhibitory agent as an agent for inhibiting estrogen synthesis brings about a lower estrogen state while maintaining QOL. Also, the treatment may be applicable to cases with no efficacy of any estrogen antagonist, post menopausal patients and male patients.
Aminoglutethimide (abbreviated to as "AG," hereinafter) having a weak aromatase inhibitory action, has been used for the treatment of some breast cancers. However, because AG has a higher potency to inhibit cleavage enzymes of cholesterol side chains and causes therefore the decrease of glucocorticoids and mineral corticoids essential for supporting life and hence supplemental therapy of these hormones is inevitable, the agent has not been applied in various fields of clinical practice.
It has been found that imidazole derivatives such as miconazole, clotrimazole and ketoconazole, which have been developed originally as antifungal agents and are now for clinical use, have aromatase inhibitory activities as well (see Biochemical Pharmacology, 34, 1087-1092, 1985). Nevertheless, these agents have not been used as therapeutical agents for treating estrogen-dependent diseases. The reason is considered that the agents do not show satisfactory specificity of the enzyme inhibition.
From the respect of their structures, aromatase inhibitory agents published in reports are grouped in steroidal agents and non-steroidal agents. Steroidal aromatase inhibitory agents include testolactone and 4-hydroxyandrostenedione, but testolactone never exerts sufficient therapeutical efficacy. These agents are poorly absorbed when administered orally, and will be also accompanied by side effects specific to steroids, so that the agents are not clinically satisfactory.
Non-steroidal aromatase inhibitory agents will now be described below in the following reports. Japanese Patent Laid-open No. Sho 61-12671 discloses N-substituted imidazoles and triazole compounds, having weak aromatase inhibitory action, but does not describe their enzyme specificity. Japanese Patent Laid-open No. Sho 61-12688 describes substituted bicyclo compounds. It is reported that CGS 16949A, one of these compounds, inhibits the biosynthesis of aldosterone, so that has no satisfactory enzyme specificity. Japanese Patent Laid-open No. Sho 63-316775 describes benzotriazole derivatives, but with no description of the enzyme specificity of these compounds. Their enzyme specificity is insufficient in a practical sense. Japanese Patent Laid-open No. Hei 1-290663 describes an N-substituted imidazole, but with no description of the activity in vivo or with no disclosure of pharmacological data concerning the specificity. However, the activity of benzyloxy-substituted imidazoles is practically lower in vivo. In other words, these prior art references do not encompass the disclosure of aromatase inhibitory activity in vivo; otherwise, the references simply disclose that their actions are weak with no satisfactory enzyme specificity. Therefore, it is not clear whether or not these compounds are clinically applicable.